Table 1.
Genetic, environmental, and lifestyle risk factors for Alzheimer disease (AD) appearance or progression.
| Non (purely) genetic risk factors | Genetic—chromosomal factors |
|---|---|
| Depression at any age and late-life depressiona | APOE4 and other gene loci, including some variants more prevalent in APOE4(+) patientsc,m, and SORL1 (neuronal apolipoprotein E receptor)o, and rare coding variants in apolipoprotein Bp |
| Type 2 diabetes mellitusa | Amyloid precursor protein (inherited AD form)d |
| Frequency of social contacts—lonelinessa | Presenilin-1 gene (inherited AD form; main cause in autosomal-dominant, early-onset AD)d,u |
| Benzodiazepines usea | Presenilin-2 gene (inherited AD form)d |
| Low adherence to Mediterranean dietb,l | Trisomy 21 (Down syndrome)e |
| Agingg | Immune (epigenetically regulated) responsef and other epigenetic eventsw |
| Anemia/Very low hemoglobin levelsh, as well as very high hemoglobin levels (U-shaped relation)x | Variants in loci in TREM2 and soluble TREM2 modulators, i.e., MS4A4A and MS4A6A, and loci in CD2AP, IQCK, ACE, ADAM10, ADAMTS1, and WWOX, and rare variantsi,j,v aggression |
| High cortical iron levels*,s and plasma ferritint | Variants in loci in IGHG3, ZNF655, GPAA1, OR8G5, IGHV3-7, SLC24A3, and lncRNA AC099552q,r |
| Grand multiparityk | Somatic brain mutations in MAPK, AMPK, and PI3K-AKT pathwayn |
| Chronic stress (psychological and biological) and inflammationg | |
| Low-density lipoprotein (LDL) cholesterolp | |
| Neuropsychiatric manifestations: psychosis, aggression/agitation, affective symptomsy | |
Sources: a [7]; b [220]; c [234]; d [235]; e [62]; f [21]; g [8]; h [236]; i [237, 238]; j [239]; k [240]; l [241]; m [242]; n [243]; o [244]; p [245]; q [246]; r [246]; s [247]; t [248]; u [249]; v [250], [251, 252]; w [253]; x [254]; y [255, 256].
*Following postmortem assessment, and mostly referring to risk for cognitive decline in already diagnosed patients with AD.